Method of preparing pregnapentaenes



United States Patent METHOD OF PREPAIkiNi PREGNAPENTAENES Milton David Heller, New City, N.Y., Robert Herman Lenhard, Ridgefield Park, N..l., and Seymour Bernstein,

New City, N.Y., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Filed July 15, 1964, Ser. No. 382,936

20 Claims. (Cl. 260-23955) wherein R is selected from the group consisting of hydroxyl and chlorine, R is selected from the group consisting of hydrogen and lower alkanoyl, R is hydrogen, methyl, fluoromethyl, difluoromethyl trifluoromethyl and fluorine, X is selected from the group consisting of chlorine and bromine and is selected from the group consisting of C}I2-OH CHzO-1OW61 alkanoyl lower alkyl HC---O lower alkyl lower alkyl C EX O-lower alkanoyl 3,274,180 Patented Sept. 20, 1966 The steroids of the present invention are substantially insoluble in water and somewhat soluble in the usual organic solvents.

The specific intermediates found useful in the process of this invention include;

,21-di-acetoXy-9a-chloro-1 1 fi-hydroxyl7a-hydr0xypregnal ,4-diene-3 ,20-dione;

21-acetoxy-9a-chloro-l 1B-hydroxy-16a,17u-isopropylidenedioxypregna-1,4-diene-3 ,20-dione;

9a-chloro-1 15,21-dihydroxy-l6a,17a-isopropylidenedi0xypregna- 1 ,4-diene-3,20-dione 21-acetoxy-9a-bromo-1 15,17a-dihydroxy-6a-methy1- pregna-1,4-diene-3 ,2 0-dione;

21-acetoxy-9a-bromo-11,8,17a-dihydroxy-6a-fluoropregna-1,4-diene-3 ,20-dione;

21-acetoxy-16ot-methyl-9a-bromo-1 1B,17a-dihydroxypregna- 1 ,4-diene-3,20-dione;

21-acetoxy-9a-bromo-l lfl,17u-dihydroXy-l6fi-methylpregna-1,4-diene-3,20-dione;

16a ,21-diacetoxy-9u,l l ,B-dichloro-l7a-hydroxypregna- 1,4-diene-3 ,20-dione;

21-acetoxy-9a,1lfi-dichloro-16a,l7a,isopropylidenedioxypregna-1,4-diene-3 ,20-dione;

9a-1 1 fl-dichloro-Z 1 -hydroxy- 1 6oz, l7a-isopr0pylidenedioxypregna-l ,4-diene-3,20-dione;

21-acetoXy-9a-11B-dic-hloro-6a-fluoromethyl-160,17aisopropylidenedioxypregna-1,4-diene-3 ,20-dione;

21-acetoxy-9a,l lfi-dichloro-6a-difluoromethyl-16a,17a-

isopropylidenedioxypregna-1,4-diene-3,20-dione;

21-acetoxy-l6a, 17a-isopropylidenedioxy-9u,1lp-dichloropregna- 1 ,4-diene-3 ,20-dione;

21-methanesulfonyloxy-9a-11fl-dichloro-16u,l7a-isopropylidenedioxy-pregna-1,4-diene-3 ,20-dione;

21-acetoXy-9a,1lfi-dichloro-17a-hydroxypregna-1,4-diene- 3,20-dione;

21-acetoxy-9et,11 S-dichloro-lM-hydroxy-l6a-methylpregna-1,4-diene-3 ,2-0-dione;

21-acetoxy-9u,115dichloro-17u-hydroxy-16B-methylpregna- 1 ,4-diene-3,20-dione;

21-acetoXy-9a,1 l fi-dichloro-l7oc-hydroxy-6 a-methylpregna- 1 ,4-diene-3,20-dione;

21-acetoxy-9u,l1 S-dichloro-6a-monoifluoromethyl-17ahydroxypregna-l ,4-diene-3,20-dione;

2 l-acetoxy-9a,1 lB-dichloro-6a-difluoromethyl-17ahydroxypregna-l ,4-diene-3 ,20-dione;

21-propionoxy-9a,1 1B-d-ichloro-6a-trifiuoron1ethyl-l7ahydroxypregna-1,4-diene-3 ,20-dione;

911,1lfi-dichloropregna-1,4-diene-3 ,20-dione;

21-hyd-roxy-9a,1 1,8-dichloro-17a-hydroxypregna-L4- diene-3,20-dione 9d,1 1 fl-diehloro-androsta- 1 ,4-diene-3,17-dione;

9oz-b1OII10-l lfi-chloro-androsta-l,4-diene-3,17-dione;

and the like.

The process of the present invention is carried out by contacting the starting material with a weak base. The weak base may be for example dimethylformamide, pyridine, collidine, lutidine, diethylpyridine and the like. The temperature of the reaction may vary from about 15 C. to about 160 C. The time tor completing the reaction will depend on the temperature used and may vary from about one-half hour to about 72 hours. After completion of the reaction, the desired steroids may be recovered by methods well known in the steroid art.

The compounds prepared by the process of the present invention are active in reducing cholesterol and therefore have utility as hypocholesteremic agents. The resulting compounds also have no appreciable activity as 3 estrogens. This lack of estrogenic activity makes them useful as hypocholesteremic agents without the undesirable estrogenic feminizing side-effects.

The following examples illustrate in detail the prep-aration of representative steroids of the present invention.

Example 1 .21-acetoxy-9a-chloro-11,8-hyalr0xy-16a,1 70cz'sop ropy liclene-dioxy pregna-Z ,4 -dz'ene-3,20-dione A stirred suspension of 4.35 g. of 9u-ChlO1'O-11fi,l6oc,-

. 17a,21-tetrahydroxypregna-1,4-diene-3,20-dione [1. Am.

Chem. Soc., 81, 1-689 (1959)] in 435 ml. of acetone is treated with 0.44 ml. of 70-72% perchloric acid. The reaction mixture is stirred at room temperature for 1.5 hours and then 6 ml. of saturated sodium bicarbonate solution and 100 ml. of water is added. After concentration under reduced pressure, 400 m1. of saturated saline solution is added and the cooled mixture is filtered and washed with water to give 4.60 g. of product, melting point 275-279" C., dec. Recrystallization from acetonernethanol-ethyl acetate gives 3.57 g. of 9a-chloro-l15-21- dihydroxy 16a,17a-isopropy lidenedioxypregna-1,4-diene- 3,20-dione, melting point 281.5283.5 C., dec.

A solution of 1.14 g. of 9a-chloro-115,21-dihydroxy- 16a,17a isopropylidenedioxypregna-1,4-diene-3,20-dione in 10 ml. of pyridine and ml. of acetic anhydride is allowed to stand at room temperature for 68 hours. The reaction mixture is poured into ice-water and the product is filtered and washed with water. Recrystallization from acetone-hexane gives 21-acet0xy-9a-chloro-1lfi-hydroxy- 1 60:,17100 isopropylidenedioxypregna-1,4-diene-3,20-dione, melting point 247249 C., the product of this example.

Example 2 .21 -acel0xy-3-hydr0xy-1 6 a,] 7 a-isopropylidenedioxy-Z9-n'0rp regna-1,3,5 ,6,8-penraen-20-0ne AMBOH 230 ma (665,800)

Example 3 .3 ,2] -diacet0xy-1 6 a,] 7a-is0p r0pylidenedi0xy- 1 9-n0'rpregna-1 ,3,5 (10) ,6,8-pen ta'anr-20-o ne A solution of 0.19 g. of 21-acetoxy-3-hydroxy-1 6a,17aisopropylidenedioxy 19-norpregna-1,3,5(-10) ,6,8-pentaen- 20-one in 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 64 hours. The reaction mixture is poured into ice-water and the resultant solid filtered and washed with water to give 0.19 g. of product. Recrystallization from acetone-hexane gives 0.13 g. of pure 3,21-diacetoxy-16a,17a-isopropylidenedioxy 19 norpregna-1,3,5-(10),6,8-pentaen-20-one, melting point 2225-2255 C.,

[a] 107 (chloroform) Example 4 .3,21 -diacet0xy-] 7a-hya r0xy-1 9-n0rpregna- 1,3,5 (10),6,8-pentaen-20-0ne A solution of 1.0 g. of 21-acetoxy-'9a-bromo-l15,1741- dihydroxypregna-l,4-diene-3,20-dione in 50 ml. of dimethylformamide is heated under reflux for 0.5 hour. The reaction mixture is evaporated under reduced pressure and the residue is dissolved in 10 ml. of pyridine and 5 ml. of acetic anhydride. After standing at room temperature overnight, methanol and benzene are added and the reaction mixture is evaporated under reduced pressure. The resultant residue is dissolved in methylene chloride and adsorbed on a synthetic magnesium silicate 4 column. Elution with 8% acetone-hexane gives 0.20 g. of product. Recrystallization from acetone-hexane gives 0.15 g. of pure 3,2l-diacetoxy-l7a-hydroxy-19-n0rpregna- 1,3,5-(10),6,8-pentaen-20-one, melting point 184.5186 C.

In this example, use of 21-a-cetoxy-9a-chloro-11fi,17adihydroxyp-regna-l,4-diene-3,20-dione [J. Am. Chem. Soc., 77, 4181 (1955)] in place of the 9a-bromo compound gives the product of the example. However, a reflux time of 22.5 hours is required.

Example 5 604,21 -diacetoxy-3 ,1 7a-dihydroxy-I9- norpregna-I,3,5 (10) ,6,8-pentaen-20-0ne A solution of 16a,21-diacetoxy-9a-bromo-115,17a-dihydroxypregna-l,4-diene-3,20-dione (1.0 g.) [1. Am. Chem. Soc., '81, 1689 (1959)] in dimethylformamide (50 ml.) is refluxed one-half hour. The solvent is removed in vacuo and the resultant oil is chromatographed on a synthetic magnesium silicate to give 16a,21-diacetoxy-3, 17a,dihydroxy-1'9-norpregna-l,3,5(10),6,8-pentaen-20-one.

Example 6.21-acet0xy-3,1 7a-dihydroxy-l 6,B-melhyl- 19-n0rpregna-1,3,5 (10) ,6,8-pentaen-20-0ne A solution of 21-acetoxy-9a-bromo-11,6,17a-dihydroxy- 16fi-methylpregn-a-l,4-diene-3,20-dione (1.0 g.) [J. Am. Chem. Soc., 80, 6687 (1958); J. Chem. Soc., 4560 (1961)] in dimethylformamide (50 ml.) is refluxed onehalf hour. The solvent is removed in vacuo and the resultant oil is chromatographed on a synthetic magnesium silicate to give 21-acetoxy-3,17a-dihydroxy-16fl-methyl- 19-norpregna-l,3,5(10),6,8-pentaen-20-one.

Example 7 .-21 -acet0xy-3,1 7adihydr0xy-1(ix-methyl- 1 9-n0rpregna-1 ,3,5 (1 0) ,6,8-perztaen-20-one A solution of 21-acetoxy-9a-brorno-11 fi,17a-dihydroxy- IGa-methylpregna-l,4-diene-3,20-dione (1.0 g.) [J. Am. Chem. Soc., 80, 4431 (1958)] in dimethylform-amide (50 ml.) is refluxed one-half hour. The solvent is removed in vacuo and water is added. The resultant oil is worked with a glass rod until a solid results. Chromatography of the solid on a synthetic magnesium silicate gives 21 acetoxy 3,17a-dihydroxy-16a-methyl-l9-norpregna- 1,3,5(10),6,8-pentaen-20-one.

Example 8 .2 1 -acetoxy-6-fla0ro-3,1 7a-dihydr0xy-19- n0rpregna-1,3,5 (1 0) ,6,8-pen taen-ZO-one A solution of 21-acetoxy-9a-bromo-6a-fluoro-1113,170;- dihydroxypregna-l,4-diene-3,20-dione (1.0 g.) [United States Patent 2,838,499 (June 10, 1958)] in dimethylformamide (50 ml.) is refluxed one-half hour. The solvent is removed in vacuo and water is added. The resultant oil is worked with a glass rod until a solid results. Chromatography of the solid on a synthetic magnesium silicate gives 21-acetoxy 6fluoro-3,17a-dihydroxy-l9-norpregna-1,3,5( 10) ,6,8-pentaen-20-one.

Example 9.21-acetoxy-3,I 7 a-dilzydr0xy-6-m'ethyl- 1 9n0rpregna-1,3,5 (1 0) ,6,8-pentaen-20-0ne Example 10.Preparati0n of 9a,Z1/3-dichl0r0-I6a,17a-

isopropylidenedioxy 21 metharzesulfonyloxypregna-I, 4-diene-3,20-di0ne A solution of 9a,]I/S-dichloro-Zl-hydroxy-16a,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione (0.72 g.) [Steroids, 1, 331 (1963)] in cold pyridine (7 ml.) is treated with methanesulfonyl chloride (0.15 ml.) and allowed to stand at 5 C. for 16.5 hours. The reaction mixture is then poured into ice water and the resultant precipitate (0.75 g., melting point 212-214 C., dec.) is filtered and washed Well with water. Crystallization from acetonehexane gives the product of the example (0.65 g., melting point 223.5 226 C., dec.). A portion of the latter is crystallized three more times from the same solvents to give melting point 232-234 C., dec.

Example 11.Preparatin of 21-chl0r0-3-hydr0xy-16a, 17a isopropylidenedioxy 19 n0rpregna1,3,5(10),6, 8-pentaen-20-one A solution of 9o 1lfi-dichloro-lfia,Hot-isopropylidenedioxy 21 methanesulfonyloxypregna-1,4-diene-3,20-dione (0.50 g.) and lithium chloride (0.14 g.) in dimethylformamide (25 ml.) is heated under reflux for 0.5 hour. The yellow solution is concentrated under reduced pressure to near dryness, water is added and the product is filtered and Washed with water to give an amorphous yellow solid (0.38 g.), melting point 90l50 C. The product is soluble in 10% sodium hydroxide solution and exhibited an equilenin-type absorption in the ultraviolet. A portion (0.365 g.) is dissolved in benzene (ca. 10 ml.) and adsorbed on a synthetic magnesium silicate (14.5 g.) column. Elution with 3% acetone-petroleum ether (boiling point 60-70") gives the product of the example (0.264 g); A 231 m (668,900), 269 m (@6570), 281 m (66570), 293 m (64800), 328 m (632.00) and 342 In (63200). The product, obtained as a white amorphous solid, is apparently labile to air or light. A solution of the product (0.13 g.) in pyridine (2 ml.) and acetic anhydride (1 ml.) is allowed to stand at room temperature for 19 hours. The solution is poured into ice water, the precipitate is filtered and washed with water to give (0.127 g.) of product, melting point 200- 203.5 C. Two crystallizations from acetone-hexane gives the analytical sample (0.109 g.) of 3-acetoxy-21- chloro 16a,17a isopropylidenedioxy 19-norpregna-1,3, 5(10),6, 8-pentaen-20-one, melting point 205 207 C.

Example 12.-Preparation of 16a,21-diacet0xy-3,I7oc-dihydroxy-19-n0 rpregna-I,3,5( -6,8-penzaen-20-0ne One gram of l6a,2l-diacetoxy-9a,llB-dichloro-17ahydroxypregna-1,4-diene-3,20-dione [Steroids, 1, 331 (1963)] in 50 ml. of dimethylformamide is reacted and worked up in the manner described in Example 2 above. The crude product is isolated, chromatographed, and crystallized from acetone-hexane to give 16a,2l-diacet0xy- 3,17a dihydroxy l9 norpregna-1,3,5(l0),6,8-pentaen 20-one.

Saponification of the product of the example with potassium carbonate in methanol followed by acidification gives 3,16a,l7a,2l-tetrahydroxy-19-norpregna-1,3,5 10) 6,8-pentaen-20-one.

Example 13.--Preparati0n 0f 21-acetoxy-3-hydr0xy-16u, 170a isopropylidenedioxy 19 n0rpregna-1,3,5(10), 6,8-pentaen-20-0ne One gram of 2l-acetoxy-9a,l1fi-diohloro-16a,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione [Steroids, 1, 331 (1963)] in 50 m1. of dirnethylformamide is reacted and worked up essentially in the manner of Example 2 above. The crude product is isolated, chromatographed, and crystallized from acetone-hexane to give 21-acetoxy- 3 hydroxy 16a,17a isopropylidenedioxy 19 norpregna- 1 ,3,5 10 ,6,8-pentaen-20-one.

Saponification of the product of the example with potassium carbonate in methanol at room temperature followed by acidification gives 3,2l-dihydroxy-16a,17aisopropylidenedioxy 19 norpregna 1,3,5(l0),6,8- pentaen-ZO-one.

Example 14.Preparati0n of 21-acet0xy-6-flu0r0methyl- 3 hydroxy 16a,17a isopropylidenedioxy 19 norpregna-1,3,5 (10) ,6,8-pentaen-20-0ne Following essentially the procedure of Example 11, the steroid 21 acetoxy 90:,11fi dichloro 60c fluoromethyl 1604,17a isopropylidenedioxypreg-na 1,4 di- 6 ene-3,20-dione (US. Patent 3,038,898) on being heated in dimethylformamide is converted into the product of the Example.

Example I5.-Preparati0n 0] 21 acetoxy 6 difluoromethyl 3 hydroxy 16a,17a isopropylidenedioxy- 19-n0rpregna-1,3,5(10),6,8-pentaen-20-0ne Following essentially the procedure of Example 11, the steroid 21 acetoxy 904,115 dichloro 60c difluoromethyl l6a,l7a isopropylidenedioxypregna 1,4 diene-3,20-dione (US. Patent 3,038,898) on being heated in dimethylformamide is converted into the product of the example.

Example 16.Preparati0n 0f 21acetoxy-6-trifluoromethyl 3-hydr0xy 16a,17a isopropylidenedioxy 19- n0rpregna-1,3,5 (10) ,6,8-pentaen-20-0ne Example 17.-Preparati0n of 21 acetoxy 3,17a dihydroxy 19 norpregna 1,3,5(10),6,8 pentwen 20- one A. A solution of 21 acetoxy 9a,115 dichloro 17ahydroxypregna 1,4 diene 3,20 dione (1.01 g.) (US. Patent 2,894,963) and lithium chloride (0.285 g.) in dimethylformamide (50 ml.) is reacted and worked up as in the preparation of 11a above to give 0.82 g. of solid. This is triturated with warm ether and filtered. The filtrate is evaporated to a glass, methanol is added and the resultant crystalline solid is filtered and washed with methanol to give the product of the example (0.207 g.), melting point 196.5 l98.5 C. One additional crystallization from acetone-hexane does not appreciably alter the melting point, 197-199 C.

B. A solution of 21 acetoxy 9a,11fi dichloro 170chydroxypregna-1,4-diene-3,20-dione (2.0 g.) and lithium chloride (0.56 g.) in d-irnethylformamide (100 ml.) is reacted and Worked up in the usual manner to give 1.50 g. of solid, melting point -155 C. A portion (1.3 g.) in pyridine (10 ml.) and acetic anhydride (5 ml.) is allowed to stand at room temperature overnight. After the addition of methanol and benzene the reaction mixture is evaporated under reduced pressure to dryness. The residue (1.35 g.) is dissolved in methylene chloride (15 ml.) and adsorbed on a synthetic-magnesium silicate (90 g.) column. Elution with 7% acetone-hexane (13 x ml. fractions) yields the 3,21-diacetate (0.34 g.), melting point 18 0- 183 C. after crystallization from acetone-hexane. Three additional crystallizations from the same solvent pair gives the analytical sample (0.27 g.) of 3,21 diacetoxy 17oz hydroxy 19 norpregna- 1,3,5(10),6,8-pentaen-20-one, melting point 184-186 C.

C. A solution of 21 acetoxy 9a,1-1[3 dichloro 17ozhydroxypregna 1,4 diene 3,20 dione (1.0 g.) in pyridine (50 ml.) is heated under reflux for 22.5 hours. The reaction mixture is evaporated under reduced pressure to a glass which is dissolved in a small amount of acetone. The addition of a large volume of water together with scratching with a glass rod precipitates 0.77 g. of solid. Trituration of the solid with warm ether is followed by filtration. The ether filtrate is evaporated to a glass. Crystallization of the residue from methanol gives 21 acetoxy 3,17a dihydroxy 19 norpregna- 1,3,5 10),6,8-pentaen-20-one (0.24 g.) melting point 193 196 C. which on recrystallization is raised to 197 199 C.

D. A solution of 21 acetoxy 901,115 dichloro 17ahydroxypregna-1,4-diene-3,20-dione (50 mg.) in dimethylforimamide is refluxed 30 minutes. The solution is concentrated to near dryness, water is added and the resultant viscous oil is worked with a glass rod until a solid is formed. Filtration gives material (30 mg.) with the identical ultraviolet and infrared spectra to the above samples of 21 acetoxy 3,17u dihydroxy 19 norpregna-1,3,5 (10) ,6,8-peutaen-20-one.

Example 18.Preparation of 3,17a,21 trihydroxy- 19-n0rpregna-1,3,5 (10) ,6,8-pentaen-20-one A solution of 21 acetoxy 3,17a dihydroxy 19- norpre'gna 1,3,5 (|10),6,8 pentaen 20 one (0.15 g.) in methanol (30 ml.) is treated with 10% aqueous potassium carbonate solution (1.5 m1.) while under an atmosphere of argon. After 30 minutes at room temperature, glacial acetic acid (0.12 ml.) is added and the reaction mixture is evaporated under reduced pressure. The residue is heated with acetone and the insoluble potassium acetate is removed by filtration. Concentration of the filtrate with simultaneous addition of hexane gives the product of the example (0.10 g.), melting point 240- 244 C. Two further crystallizations from acetone-hexane gives the analytical sample (0.07 g.), melting .point 245249 C.

Example 19.--Preparation of 19-n0rpregna-I,3, (),6,8-pentaen-3,l 7 a,20,21 -tetr0l A solution of 3,17u,21 trihydroxy 19 norpregna- 1,3,5 (10),6,8-pentaen-20-one (0.024 g.) and sodium borohydride (0.024 g.) in absolute ethanol (2 ml.) and one drop of water is allowed to stand at room temperature for one hour. It is then neutralized with dilute sulfuric acid, diluted with water and extracted with ethyl acetate. The extract is washed with saturated saline, dried over magnesium sulfate and evaporated under reduced pressure to give crude 19 norpregna-1,3,5(10),6,8-pentaen- 3,17a,20,21-tetr0l (0.019 g.), melting point 2082l4 C. with previous softening.

Example 20.Pr parati0n of 21-acetoxy-3,1 7a-dihya'roxy- 1 6a-methyl-19-n0rpregna-I,3,5 (1 0 ,6,8-pentaen-20-0ne A solution of 1.0 g. of 21-acetoxy-9a,11B-dich1oro-17ahydroxy-l6a-methylpregna-L4 diene 3,20 dione (U.S. Patent No. 2,894,963) in 50 ml. of dimethylformamide is reacted and worked up as described in Example 17D above. The crude product is isolated, chromatographed and crystallized from acetone-hexane to give 21-acetoxy- 3,170: dihydroxy-l6a-methyl-19-norpregna-1,3,5(10),6,8- pentaen-ZO-one.

Example 21.--Preparati0n of 21-acet0xy-3,1 7a-dihydroxy- 1 6fl-methyl-19-n0rpregna-1,3,5 (10) ,6,8-pentaen-20-o'ne A solution of 1.0 g. of 21-acetoxy-9a,llfl dichloro-lhhydroxy-l6 3-methylpregna-L4 diene 3,20 dione (U.S. Patent No. 2,894,963) in 50 ml. of dimethylform-amide is reacted and worked up as described in Example 17D above. The crude product is isolated, chromatographed, and crystallized from acetone-hexane to give 21-acetoxy- 3,17a dihydroxy-16fi-methyl-19-norpregna-1,3,5 10) ,6,8- pentaen-20-one.

Example 22.-Preparation 0 f 21-aeet0xy-3,1 7 a-dihydroxy- 6-methyl-19-n0rpregna-1,3,5 (10) ,6,8-pentaetn-20-0ne One gram of 21-acetoxy-9'a,11B-dichloro-17a-hydroxy- 6a-methylpregna-1,4-diene-3,20-dione (U.S. Patent No. 2,894,963) in 50 ml. of dimethylformamide is reacted and worked up in the manner of Example 17D above. The crude product is isolated, chromatographed and crystallized from acetone-hexane to give 21-acetoxy-3,l7adihydroxy 6-methyl-19-norpregna-1,3,5 10) 6,8-pentaen- 20-one.

Example 23.Preparation of 21-acet0xy-6-m0noflu0-r0- methyl 3,1704 dihydroxy-l9-norpregna-J,3,5(10),6,8- pentaen-ZO-one Followingthe procedure described in Example 17D 21 acetoxy 911,11fl-dichloro-6a-monofluoromethy1-17ahydi-oxypregna-1,4-diene-3,20-dione (U.S. Patent No. 3,038,898) is converted into the product of the example by heating with dimethylformamide.

Example 24.Preparati0n of 21-acet0xy-6-diflu0r0methyl-3,17a-dihydr0xy-J9-norpregna-1,3,5(10),6,8-pentaen- 20-0ne Following the procedure of Example 17D 21-acetoxy- 9a,11fi dichloro 6a-difluoromethyl-17a-hydroxypregna- 1,4-diene-3,20-dione (U.S. Patent No. 3,038,898) is converted into the product of the example by heating with dimethylformamide.

Example 25.Preparati0n of 21-pr0pi0n0xy-6-trifluor0- methyl 3,17a dihydr0xy-19-n0rpregnw-1,3,5(10),6,8- pentaen-ZO-ane Following the procedure described in Example 17D 21 propionoxy 9a,l1,8-dichloro-6a-trifiuoromethyl-17ahydroxy-pregna-1,4-diene-3,20-dione (U.S. Patent No. 3,038,898) is converted into the product of the example by heating with dimethylformamide.

Example 2 6.Preparati0n of 3-hydr0xy-19-n0rpregna- 1,3,5 (10),6,8pentaen-20-0ne Using the procedure of Example 17D 9a,11/3-dichloro pregna-1,4-diene-3,20-dione [1. Am. Chem. Soc., 82, 2308 (1960)] is converted into the product of the example by heating with dimethylformamide.

Example 27.Preparation of 21-acet0xy-9a,IIii-dichloro- 6 a-fluoro-I 7a-hydr0xypregna-1 ,4-diene-3,20-di0rze A stirred solution of 0.25 g. of 21-acetoxy-6u-fluoro- 17a-hydroxypregna-1,4,9(11)-triene 3,20 dione (U.S. Patent No. 2,838,499) and 1.0 g. of lithium chloride in 10 ml. of glacial acetic acid is cooled to 510 C. and is treated with 0.091 g. of N-chlorosuccinimide followed by 0.25 ml. of a saturated solution of anhydrous hydrogen chloride in tetrahydrofuran. After stirring at room temperature for 3 hours, the reaction mixture is poured into ice-water and the crude product is filtered and washed with water. The moist solid is dissolved in methylene chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 0.27 g. of the product of this example. Recrystallization from methylene chloride-methanol gives the pure 2l-acetoxy-9a-llfidichloro 60c fluoro-l7a-hydroxypregna-1,4-diene-3,20- dione; M.P. 248-250 C. dec.; +l2l (pyridine);

W 234. mp (615,500)

A solution of 1.0 g. of 21-acetoxy-9a,11 fi-diChlOTO-6ozfluoro-l7vt-hydroxypregna-1,4-diene-3,20dione in 50 ml. of dimethylformamide is heated under reflux for 30 minutes. The yellow-orange solution is evaporated under reduced pressure to dryness, water is added and the resulant oil is scratched with a glass rod to afford 0.756 g. of solid. Trituration of the solid With warm ether is followed by filtration. The ether filtrate is evaporated to a glass (0.476 g.) which is dissolved in methylene chloride and adsorbed on a synthetic magnesium silicate column. Elution with 10% acetone-hexane gives 0.107 g. of 21-acetoxy-6-fluoro-3,17a-dihydroxy-19-norpregna- 1,3,5 10) ,6,8-pentaen-20-one.

Example 29.Preparation of 3 ,21 -diaoet0xy-6-flu0ro-1 7 ahydroxy-19-n0rpregna-1,3,5 (1 0) ,6,8-pentaen-20-one A solution of 0.107 g. of 21-acetoxy-6-fluoro-3,17ot-dihydroxy-19-norpregna-1,3,5(l0),6,8-pentaen-20-one in 2 ml. of pyridine and 1 ml. of acetic anhydride is allowed to stand at room temperature overnight. The addition of ice-water followed by filtration affords 0.10 g. of solid which is dissolved in methylene chloride and chromatographed on a synthetic magnesium silicate. Elution with 7% acetone-hexane gives 0.077 g. of product. Recrystallization from acetone-hexane affords pure 3,21-diacetoxy- 6 fiuoro 17a-hydroxy-19-norpregna-1,3,5(10),6,8-pentaen-ZO-one; melting point 203-205.5 C.

Example 30.Preparafin of 6-flu0r0-3-hya'r0xy-19-n0rpregna-J ,3 ,5 1 0) ,6,8-penmen-2 O-one Example 31.-,-Preparati0n of 3-hydr0xyestra-1,3,5 (10),6, 8-pentaen-17-0ne (equilenin) A solution of 904,1lfi-dichloroandrosta-l,4-diene-3,17- dione (0.200 g.) [1. Am. Chem. Soc., 81, 21911 (1959)] and lithium chloride (0.06 g.) in dimethylformarnide (10 ml.) is heated under reflux for 30 minutes. The reaction mixture is concentrated under reduced pressure to near dryness, water is added and the resultant viscous oil is converted to a tan solid by scratching With a glass rod. The solid is filtered and Washed with water to give 0.117 g., melting point 140-220 C. (red melt). This material is dissolved in methylene chloride (ca. 10 ml.) and adsorbed on a synthetic magnesium silicate (12 g.) column. Elution with acetone-petroleum ether (boiling point 6070 C.) x 15 ml. fractions) gives, in the initial 200 ml. of eluate, equilenin (0.024 g.) as indicated by infrared spectral and thin-layer chromatographic analyses. Crystallization from acetone-hexane gives 0.017 g. of equilenin melting point 239-2 45 0., red melt. The remaining 300 ml. of eluate on evaporation yields 0.088 g. of a mixture of equilenin and one or more by-products as indicated by infrared and thin-layer chromatographic analyses. The mixture is combined With the evaporated mother liquor above and chromatographed on diatomaceous earth using a solvent system consisting of n-heptane saturated With methanol. The solid (0.037 g.) obtained on evaporation of holdback volume 5 through 6.5 is crystallized from acetone-hexane to give an additional 0.020 g. of equilenin, melting point 242.5250 C. the latter is combined with the fraction obtained from the adsorption chromatography above and is recrystallized from the same solvent pair to give 0.024 g., melting point 244.5 250 C. *One additional crystallization from ethanolwater gives 0.015 g. of equilenin, melting point 246.5 250 C.,

mm 230 m (660,400)

269 rn,u ($4790), 280 I'll/L (@5550), 292 mu (E3720), 327 my. (E2290) and 339 mp. (c2560);

'vKBr 3285, 1722, 1627 and 1602 emf, [6!]D+89O (dioxane) In the above experiment lithium chloride can be omitted and the product, equilenin, is obtained in a comparable yield.

Example 32.Preparazi0n 0f 3-hydr0xyestra1,3,5 (]O),6, 8-pentaen-I 7-0ne A solution of 9a-bromo-11/3-chloroandrosta-1,4-diene- 3,17-dione (0.200 g.) [J. Am. Chem. Soc., 81, 2191 (1959)] in dimethylformamide (1-0 ml.) is heated under 10 reflux for 30 minutes. The desired equilenin is isolated by chromatography in a manner similar to that described in Example 31.

We claim: 1. A method of preparing compounds of the formula:

wherein R is selected from the group consisting 0t hydrogen and lower alkanoyl, R is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or fluorine and is selected from the group consisting of ?H O H CHz-O1OW9I alkanoyl (3:0 (i=0 0 0 H /O O H JiIC 0 H H (ll-O -lower alkanoyl (IJH -OI C H O-lower alkanoyl (|)=H C=O C 0 lower alkyl C 0 lower alkyl 0 0 lower alkyl lower alkyl which comprises contacting a steroid of the formula:

wherein R and is as defined above and X is selected from the group consisting of chlorine and bromine and R is selected from the group consisting of hydroxyl and chlorine, With a Weak base at a temperature Within the range of about 15 C. to about C. and recovering said product therefrom.

2. A method of preparing 1 6a,21-di1ower alkanoyloxy- 3,17ot-dihydroxy-19 norpregna 1,3,5 (10),6,8 pentaen 20-one which comprises contacting 16a,21-di1ower alkanoy1oxy-9a-ch1oro-115, 170 dihydroxy pregna 1,4 diene-3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

3. A method of preparing 21-acetoxy-3-hydroXy-16a, 17oz isopropylidenedioxy 19 norpregna 1,3,5(10),6,8- pentaen-20-one which comprises contacting 2:1-acetoxy- 9oc-Chl01'0 11p hydroxy 16 170; isopropylidenedioxypregna-l,4-diene-3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

4. A method of preparing 3,12-diacetoxy-17a-hydroxy- 19-norpregna-1,3,5(10),6,8-pentaen-20-one which comprises contacting 21 acetoxy 9a bromo-11fl,17a-dihydroxypregna 1,4 diene-3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C., subsequently treating with pyridine and acetic anhydride and recovering said compound therefrom.

5. A method of preparing 16a,21-diacetoxy-3,17a-di hydroxy 19 norpregna 1,3,5 (),6,8-pentaen-20-one which comprises contacting 1601.,21-d1aC6iOXy-90Fb1'OII10- 11,8,l7a-dihydroxypregna-1,4-diene-3,20-dione with di methylformarnide at a temperature within the range of about C. to about 160 C. and recovering said compound therefrom.

6. A method of preparing 21-acetoXy-3,17a-dihydroxy- 1618 methyl-19-norpregna-1,3,S(10),6,8-pentaen-20-one which comprises contacting 21-acetoxy-9a-bromo-11B, 17oz dihydroxy 16,8-methylpregna-1,4-diene-3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

7. A method of preparing 21-acetoXy-3,17u-dihydroXy- 16a methyl 19-norpregna-1,3,5(10),6,8-pentaen-20-one which comprises contacting 21-acetoxy-9a-bromo-11B, 170a dihydroxy 16a-methy1pregna-1,4-diene-3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

8. A method of preparing 21-acetoxy-6-fluoro-3,17adihydroxy 19 norpregna-1,3,5(10),6,8-pentaen-20-one which comprises contacting 21-acetoXy-9a-bromo-6afluoro 1113,1711 dihydroxy-pregna-l,4-diene-3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom. V

9. A method of preparing 21-acetoXy-3,17ot-dihydroxy- 6 methyl 19 norpregna-1,3,5(10),6,8-pentaen-20-one which comprises contacting 21-acetoXy-9a-bromo-11B, 17a-dihydroxy-6a-methylpregna-1,4-diene-3 ,20-dione with dimethyifo-rmamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

10. A method of preparing 16oc,21-di2166t0XY-3,170cdihydroxy 19 norpregna-1,3,5(10),6,8-pentaen-20-one which comprises contacting 16a,21-diacetoXy-9a,1lp-dichloro-17ot-hydroxypregna-1,4-diene-3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

11. A method of preparing 21-acetoxy-3-hydroxy- 1611,1705 isopropy-lidenedioxy-19-norpregna-1,3,5(11)),6, S-pentaen-ZO-one which comprises contacting 21-acetoxy- 90:,115 dichioro-16a,l7a-isopropylidenedioxypregna-1,4- ene3,20-dione with dimethylformamide at a tempera.-

12 ture within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

12. A method of preparing 21-ch1oro-3-hydr0xy-16a, 17oz isopropylidenedioxy 19 norpregna-1,3,5(10),6,8- pentaen-ZO-one which comprises contacting 9a,11/3-dichloro 21 hydroxy-l6a,17a-isopropylidenedioxypregna- 1,4-diene-3,20-dione with methanesulfonyl chloride and subsequently with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

13. A method of preparing 21-acetoxy-6-fiuoromethy1- 3 hydroxy 16a,17a-isopropy1idenedioxy-19-norpregna- 1,3,5(10),6,8-pentaen-20-one which comprises contacting 21 acetoxy 904,115 dich1oro-6a-fluoromethy1-1611,17- isopropylidenedioxypregna-1,4-diene-3,ZO-dione with dirnethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound thereform.

14. A method of preparing 21-acetoxy-3,17a-dihydroxy-19-norpregna-1,3,5 10) ,6,8-pentaen-20-one which comprises contacting 21-acetoxy-9a,11B-dich1oro-17a-hydroxypregna 1,4 diene-3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

15. A method of preparing 21-acetoXy-3,17u-dihydroxy 16a methyl-19-norpregna-1,3,5(10),6,8-pentaen- 20-one which comprises contacting 21-acetoxy-9a,11 8-dichloro 17a. hydroxy-l6a-methy1pregna-1,4-diene-3,20- dione with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

16. A method of preparing 21-acetoxy-6-trifiuoromethyl 3 hydroXy-16u,17u-isopropy1idenedioxy-19-norpregna-1,3,5(10),6,8pentaen-20-one which comprises contacting 21-acetoXy-9ot,1 1,B-dichloro-6a-triflu0romethyl- 160 1711 isopropyiidenedioxypregna-1,4-diene-3,20-dionc with dimethylformamide at a temperature within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

17. A method of preparing 21-acetoXy-3,17a-dihydroxy 6-methyl-19-norpregna-1,3,5 (10),6,8-pentaen-20- one which comprises contacting 21-acetoXy9a,11B-dichloro 17a hydroxy 6a-methy1pregna-1,4-diene-3,20- dione with dimethylformamide at a temperature Within the range of about 15 C. to about 160 C. and recovering said compound therefrom.

18. A method of preparing 6-fluoro-3-hydroXy-19- norpregna-l,3,5(10),6,8-pentaen-20-one which comprises contacting ,11fi dichloro 6a-fluoro-pregna-1,4-diene- 3,20-dione with dimethylformamide at a temperature within the range of about 15 C. to about C. and recovering said compound therefrom.

19. A method of preparing 3-hydroXyestra-1,3,5(10), 6,8-pentaen-17-one which comprises contacting 9ot,11fidichloroandrosta-1,4-diene-3,17-dione with dimethylformamide at a temperature within the range of 15 C. to about 160 C. for a period of from about one-half hour to about 72 hours.

20. A method of preparing 3-hydroXyestra-1,3,S(10), 6,8-pentaen-17-one which comprises contacting 9a-bromo- 1lfl-chloroandrosta-1,4-diene-3,17-dione with dimethylformamide at a temperature within the range of 15 C. to about 160 C. for a period of from about one-half hour to about 72 hours.

No references cited.

LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3,274,180 September 20, 1966 Milton David Heller et alo It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 10, line 32, fifth structural formula, strike out "C=H" and insert instead C=O column 11, line 15, for "3,12-diacetoxy-l7on=hydroxy" read 3,2l-diacetoxy-l7uhydroxy- Signed and sealed this 22nd day of August 19670 (SEAL) Attest: ERNEST W. SWIDER EDWARD J. BRENNER Anesting Officer Commissioner of Patents 

1. A METHOD OF PREPARING COMPOUNDS OF THE FORMULA: 3-(R''-O-),6-R2-ESTRA-1,3,5(10),6,8-PENTAENE WHEREIN R'' IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKANOYL, R2 IS HYDROGEN, METHYL, FLUOROMETHYL, DIFLUOROMETHYL, TRIFLUOROMETHYL OR FLUORINE AND -C17-C16- OF RING IS SELECTED FROM THE GROUP CONSISTING OF -C(-CO-CH2-OH)(-OH)-CH(-OH)-; WHICH COMPRISES CONTACTING A STERIOD OF THE FORMULA: 6-R2,9-X,11-R-ANDROSTA-1,4-DIEN-3-ONE WHEREIN R2 AND -C17-C16- OF RING -C(-CO-CH2-O-LOWER ALKANOYL)(-OH)-CH(-O-LOWER ALKANOYL)-; -(2,2-DI(LOWER ALKYL),4-(CL-CH2-CO-)-1,3-DIOXOLAN-4,5YLENE)-; -(2,2-DI(LOWER ALKYL),4-(LOWER ALKANOYL-O-CH2-CO-)-1,3DIOXOLAN-4,5-YLENE)-; -C(-CO-CH2-O-LOWER ALKANOYL)(-OH)-CH2-; -C(-CO-CH2-O-LOWER ALKANOYL)(-OH)-CH(-CH3)-; -C(-CO-CH2-OH)(-OH)-CH2-; -CH(-CO-CH3)-CH2-; -CO-CH2IS AS DEFINED ABOVE AND X IS SELECTED FROM THE GROUP CONSISTING OF CHLORINE AND BROMINE AND R IS SELECTED FROM THE GROUP CONSISTING OF HYDROXYL AND CHLORINE, WITH A WEAK BASE AT A TEMPERATURE WITHIN THE RANGE OF ABOUT 15* C. TO ABOUT 160*C. AND RECOVERING SAID PRODUCT THEREFROM. 